DK162508B - PHARMACEUTICAL PREPARATION CONTAINING A BENZENDIOL DERIVATIVE AND PROCEDURE FOR ITS PREPARATION - Google Patents

Description

DK 162508 B

The invention relates to a novel pharmaceutical composition in the form of an aqueous solution suitable for freeze-drying. The invention further relates to a unit gasket containing such a solution, a process 5 for preparing a solid form of the active ingredient herein, and a freeze-dried preparation containing the active ingredient.

The composition of the invention is characterized in that it contains as active ingredient 0.5 - 10% w / v (measured as the hydrochloride salt) of 4- [2- (6- (2-phenylethylamino) hexylamino) ethyl] -1,2 -benzenediol or 4- [2- (6- (2- (4-chlorophenyl) ethylamino) -hexylamino) ethyl] -1,2-benzenediol or a pharmaceutically acceptable acid addition salt thereof and a physiologically acceptable acid, the pH of the solution being value is higher than 1.5 and lower than 3.5.

It is preferred that the active ingredient be in the form of an acid addition salt. Suitable salts include salts of mineral acids, for example hydrogen halide acids such as hydrochloric or hydrobromic acid, or organic acids, e.g. formic acid, acetic acid or lactic acid. The acid may be polybasic, for example sulfuric acid, fumaric acid or citric acid. It is also preferred that the mixture contains the former active ingredient.

The active ingredients can be prepared by the methods described in Examples 1 and 2. Salts other than those described in Examples 1 and 2 can be prepared from the salts disclosed in Examples 1 or 2 or out of the free bases by conventional techniques, e.g. ion exchange ter-chroma tograf i.

The composition of the invention preferably has a pH lower than 3.0 and preferably a pH higher than 2.

Particularly preferred is a solution having a pH of from 2 to 3, e.g. ca. 2.5.

Surprisingly, it has been found that acidic solutions of the active ingredient are more stable than neutral or basic solutions.

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It is preferred that the solution according to the invention be substantially free of dissolved oxygen. It is also preferred that it is substantially free of metal ions different from the metal ions of group 1a of the periodic system. In particular, it is preferred that the solution in question be substantially free of transition metal ions, in particular copper, chromium and iron. By substantially free is meant less than 20 ppm, preferably less than 10 ppm and especially less than 5 ppm of the metal ions.

The solutions in question are generally too acidic for direct use to the body, but may be diluted appropriately, e.g. with injection water or isotonic saline, to obtain solutions with a physiologically acceptable pH, e.g. with a pH of from 4 to 8.

The concentration of the active ingredient in the solution of the invention will vary with the active ingredient and with the particular salt used. However, an active ingredient concentration (determined as hydrochloride salt) of 1.0 to 5.0% is preferred, and in particular about 20%. 2.0% w / v.

The concentration of the acid in the present solution will be such that the desired pH is obtained.

The physiologically acceptable acid may be any suitable organic or inorganic acid. The acids are preferably suitable for use by injection or infusion.

Mentionable acids include hydrochloric, ascorbic, wine, apple, maleic and citric acids.

A solution containing a mixture of an active ingredient and a physiologically acceptable acid can, if desired, be evaporated, e.g. by freeze-drying or spray-drying, to form e: t solid composition. The solution is preferably sterile filtered and / or autoclaved prior to evaporation. Solid preparations are advantageous in that they do not require the transport of large volumes of water and that they can be prepared immediately before use.

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Surprisingly, it has been found that aqueous solutions of the invention can be lyophilized to form a solid composition containing fewer degradation products of the active ingredient than is the case with lyophilization of neutral or basic solutions of the active ingredient.

Accordingly, the process of the invention for preparing a solid form of an active ingredient as defined above is peculiar to the characterizing part of claim 5 and the lyophilized composition of the invention is peculiar to the characterizing part of claim 6.

The solution to be evaporated may contain a volatile acid, e.g., hydrochloric acid, or a non-volatile acid, e.g. ascorbic acid. The solid preparation prepared by evaporation can be reconstituted, e.g. with sterile, isotonic saline or with water for injection. Such reconstituted solutions may, if necessary, be buffered at a pH suitable for direct intravenous infusion, e.g. at a pH of 4 to 8, in particular 4.5 to 7.5, or at a pH between 1.5 and 3.5, for subsequent dilution with e.g. isotonic saline. Alternatively, when the acid is non-volatile, the solid composition can be reconstituted by adding an appropriate amount of water, preferably sterile demineralized water, to form an aqueous solution which is approximately similar to the original solution with respect to pH.

Reconstitutable solid compositions prepared by evaporation of solutions 30 of the invention may be packaged in suitable pharmaceutical equipment, e.g. syringes, infusion containers or ampoules so that the addition of sterile isotonic saline allows ± n situ preparation of an aqueous solution of active ingredient in a form suitable for immediate administration to a patient.

The aqueous compositions may contain other excipients in addition to the active ingredient and the acid. In particular, mention may be made of antioxidants, f.

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DK 162508 B

sodium metabisulphite, chelating agents, e.g. mono- or di-sodium edetate, sodium chloride and buffering agents, e.g. sodium citrate. It is preferred to avoid the use of phosphate buffers, as these hairs have been shown to promote degradation of the active ingredients in aqueous solution. The solution may also, if desired, contain a reducing sugar, e.g. · dextrose. When a subject solution is intended for evaporation into a reconstitutable powder, it may also contain a physiologically acceptable inert filler, e.g. mannitol.

The solutions of the invention can be prepared by dissolving the active ingredient and any excipients in water, preferably deoxygenated water, and adjusting the pH to the desired value by adding the preferred acid or mixture of acids. The solution can be sterilized, e.g. by filtration or by autoclaving, and, if desired, evaporating, e.g. freeze-dried, using conventional technique to obtain a solid. The solid mixture can be reconstituted, e.g. with deoxygenated water or injection water, BP, as desired, to obtain solutions of the mixtures.

When the components included in the solution of the invention are non-volatile solids, e.g. when the acid is ascorbic acid and the active ingredient is a hydrochloride salt, the mixture can be prepared by admixing, e.g. comminuted, the components.

When storing the solutions or solid compositions of the invention, it is preferred to store the solution mixtures in neutral glass vials that are surface treated to reduce contamination with metal ions. A particularly suitable treatment method is to first wash the vial with aqueous acid solution followed by washing with 3% w / v aqueous ammonium sulfate solution. Alternatively, the vials may be washed with an acidified ammonium sulfate solution. Solid mixtures are preferably stored in neutral glass medicine bottles.

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It is preferred that the present solutions be sealed in surface-treated ampules of 0.5 to 25 ml, preferably 1 to 10 ml, and most preferably 2 to 5 ml. In particular, a 2% w / v aqueous composition of the active ingredient sealed in a vial having a capacity of between 1 and 10 ml is preferred, e.g. in ampoules of 2 or 5 ml. The vials are preferably filled under nitrogen.

The present compositions are preferably stored at room temperature and protected from light.

According to the invention, there is also provided a unit gasket containing a solution as defined above, the gasket being characterized by the characterizing part of claim 4.

The active ingredients are useful because of their pharmacological activity on animals. Thus, the compounds act on peripheral and / or central dopamine receptors. Because of this property, they lower blood pressure, decrease heart rate and increase blood flow to certain vascular layers, e.g. renal layers. The compounds also have an effect on other adrenoreceptors and exhibit cardiac stimulating and bronchodilatory effects. The activity of the compounds is observed in the following test systems: (a) renal blood flow in dogs, McNay and Goldberg, J.Pharmac.Exp.Ther., 151, 23-31, 1966, (b) isolated rabbit ear artery, McCullogh, Rand and Story,

Br.J.Pharmac., 49, 141-142, 1973, and (c) cat cornea membrane, Gyorgy and Doda, Arch. Int.

Pharmacodyn., 226, 194-206, 1977.

The compounds are useful in the treatment of congestive heart failure, kidney failure, angina pectoris, ischemic heart disease, hypertension, reversible obstructive airway disease, hyperprolactinaemia, and also in Parkin ^ - 35 son's disease and other neurological diseases.

The dose used will depend on the active ingredient used, the mode of application and the desired effect.

Generally, however, satisfactory re- 6 is obtained

DK 162508 B

results when the compounds are used at a dose of 0.05 µg to 50 mg per kg body weight per day. In humans, the prescribed total daily dose ranges from 2.5 µg to 3.5 g, which can be administered in divided doses 5, for example, from 1 µg to 750 mg.

The active ingredients have the advantage that they are very effective or cause less undesirable side effects in certain pharmacological models or have a longer lasting effect than compounds of similar structure.

The compositions of the invention may be administered by a variety of routes and may act systemically or locally. Thus, the compounds may be administered by oral or nasal inhalation to the lungs, to the oral cavity, esophagus, rectally, topically on the skin or other available body surfaces, but are preferably used as solutions by infusion, e.g. intravenously.

When the active ingredient is used for intravenous infusion, an infusion rate is recommended for humans in the range of 0.1 to 20, preferably from 0.5 to 10 µg of active ingredient (determined as hydrochloride salt / kg body weight / minute). given continuously or intermittently, as desired, for periods of, for example, 0.5 to 48 hours.

The invention is further described by the following 25 preparations, examples and stability tests.

Preparation 1 4- [2- (6- (2-Phenylethylamino) hexylamino) ethyl] -1,2-benzenediol.

(A) N- [2- (3,4-Dimethoxyphenyl) ethyl] -N '- [2-phenylethyl] hexane-1,6-diamide.

A solution of 6-oxo-6- (2- (3,4-dimethoxyphenyl) ethylamino) hexanoic acid (9.3 g) and N 2 '- carbonyldiimidazole (4.90 g in dry dichloromethane (300 ml) was stirred at A solution of 2-phenylethylamine (3.8 ml) in dichloromethane (50 ml) was added and the mixture was stirred at room temperature for 3 hours.

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The solution was washed with 2N hydrochloric acid, water, 5% aqueous sodium bicarbonate solution and water. The organic phase was dried over magnesium sulfate, filtered and evaporated to give a solid crystallizing from ethanol (11.38 g), m.p. 183-184 ° C.

(b) N- [2- (3,4-Dimethoxyphenyl) ethyl] -N '- [2-phenylethyl] -hexane-1,6-diamine dihydrochloride.

A solution of the diamide product of step 1 (a) (4.94 g) in dry tetrahydrofuran (150 ml) was stirred under a nitrogen atmosphere while diborane was added in tetrahydrofuran (48 ml of 1M solution). The solution was heated at reflux for 24 hours.

Methanol (100 ml) was added to the cooled solution. The mixture was evaporated to dryness. The evaporation residue was dissolved in methanolic HCl (100 mil and heated under reflux for 1 hour. The solution was evaporated and the solid was crystallized from methanol (4.90 g, mp 283-285 ° C.

(c) 4- [2- ((2-Phenylethylamino) hexylaminolethyl] - * - 1,2-benzenediol dihydrobromide.

A solution of the diamine product of step (b1 (4.75 g in 48% aqueous hydrobromic acid (70 ml) was heated under reflux in a nitrogen atmosphere for 3.5 hours).

The solid formed by cooling was filtered off and crystallized from ethanol to give the title compound as dihydrobromide salt (3.1 g), m.p. 227R-228 ° C,

Preparation 2 4- [2- (6- (2- (4-Chlorophenyl) ethylamino) hexylamino) ethyl]-1,2-benzenediol.

(a) N- [2- (3,4-Dimethoxyphenyl) ethyl] -N '- [2- (4-chlorophenyl) ethyl] hexane-1,6-diamide.

The subtitle compound was prepared by the method of Preparation 1 (a), m.p. 167-169 ° C.

(B) N- [2- (3,4-Dimethoxyphenyl) ethyl] -Ν '- [2- (4-chlorophenyl) ethyl] -hexane-1,6-diamine.

The subtitle compound was prepared by the method of Preparation 1 (b), m.p. 260 ° C.

DK 162508 B

s (c) 4- [2- (6- (2- (4-Chlorophenyl) ethylamino) hexylamino] ethyl] -1,2-benzenediol dihydrobromide,

The title compound was prepared as a dihydro-bromide salt by the method of Preparation i (cl

Preparation 3 4- [2- [6- [2- (4-Chlorophenyl) ethylamino] hexylamino] ethyl] -1,2-benzenediol dihydrochloride.

4- [2- [6- [2- (4-Chlorophenyl.) Ethylamino] hexylamino] -ethyl] -1,2-benzenediol dihydrobromide (3, 10 g) was dissolved in a minimal amount of water and saturated sodium bicarbonate was added. was added until the pH of the solution was about 8. The precipitated free base was washed with ice-cold water and then suspended in concentrated hydrochloric acid and stirred with gentle heating until all the sticky material was replaced by a fine white The suspension was cooled in ice and filtered and the precipitate was recrystallized from ethanol to give the title dihydrochloride (2.0 g as white crystals, mp 186-188 ° C).

Found: Cl: 23.02%, the dihydrochloride requires Cl in 22.93%.

Preparation 4 4- [2- [6- (2-Phenylethylamino) hexylamino] ethyl] -1,2-benzenediol dihydrochloride.

The title compound was prepared from the corresponding dihydrobromide salt by the procedure of Example 3, m.p. 219 to 219.5 ° C.

30

Example

Intravenous preparations

Demineralized pyrogen-free water was deoxygenated with nitrogen and added to the active ingredient and excipients. Sufficient acid was added to the solution to obtain the desired pH, the solution was sterilized under nitrogen in neutral glass ampoules of 2 or 5 ml. The ampoules were 9

DK 162508 B

then sealed and stored at room temperature protected from light. As an alternative to sterile filtration, sealed ampoules can be autoclaved for 15 minutes at 121 ° C.

The vials were surface treated by washing with 3% w / v ammonium sulfate acidified to pH 2 with 6M hydrochloric acid.

Preparation 1% w / v Compound according to Preparation 4 2.0

Disodium EDTA 0.01 0.01M Hydrochloric acid to pH 2.5

Water to 100 15 Preparation 2

Compound of Preparation 3 2.0

Disodium EDTA 0.01 0.01M Hydrochloric acid to pH 2.5

Water for 100 20

Preparation 3% w / v

Compound of Preparation 4 2.0

Disodium EDTAt 0.01

Dextrose 5.0 25 6M Hydrochloric acid to pH 2.5

Water to 100

Preparation 4

Compound of Preparation 4 2.0 30 Sodium Metabisulfite 1.0

Dextrose up to 5.0 6M Hydrochloric acid to pH 2.5

Preparation 4 is preferably sterilized directly into ampoules or autoclaved in ampoules.

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Freeze-dried preparations

Aqueous solutions of the invention were prepared as described above. The solution was then sterile filtered and lyophilized to give a solid preparation. The solid composition may be packaged in sealed containers, e.g. a folded container equipped with a partition or an appropriately arranged syringe pack or infusion container.

10 Preparation. 5% w / v

Freeze-drying solution:.

Compound of Preparation 4 2.0

Mannitol 3.0

Disodium edetate 0.01 15 6M Hydrochloric acid to pH 3.0

Water to 100

Freeze drying gave a solid of the following composition: 20

Compound of Preparation 4 39.92% by weight

Mannitol 59.88% by weight

Disodium edetate 0.20 wt% 25 Preparation 6% w / v

Freeze-drying solution;

Compound of Preparation 4 2.0

Ascorbic Acid 0.2

Water to 100 30

Freeze drying gave a solid of the following composition;

Compound of Preparation 4 90.91 wt% Ascorbic acid 9.09 wt%.

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stability Testing

The compound prepared in Preparation 4; 4- [2- (6- (2-Phenylethylamino) hexylamino) ethyl] -1,2-benzenediol, dihydrochloride (hereinafter called Compound A) was tested for stability at pH values 2, 4 and 8, in measuring the presence of its degradation products adrenochrome and adrenolutin.

As can be seen from the scheme below, Compound A undergoes oxidation and forms the adrenochrome derivative (B), the pink color of which can be seen in decomposed solutions of Compound A. Under alkaline conditions, adrenochrome undergoes rearrangement to form the adrenolate derivative (C).

Compound A and its derivatives B and C can be easily detected by HPLC.

30 HoAJ

Compound A

- Η Η £

35 The following aqueous solutions of compound A

were prepared and stored in the dark in acid-cleaned glass containers flushed with He at 37 ° C and 60 ° C, respectively.

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1) 1.0% solution in 0.3% HCl, pH 2; 2) 1.0% solution in distilled water, pH 4; and 3) 1.0% solution in 1.0% m / v aqueous sodium bicarbonate solution, pH 8.

Each sample was analyzed by HPLC after 1 and 5 days under the following conditions:

Column: Hypersil 50DS;

Mobile phase A: 0.01 M aqueous dibutylamine phosphate; Mobile phase B: 0.01 M dibutylamine phosphate in 60% v / v aqueous acetonitrile;

Temperature: 30 ° C; 3

Flow rate: 1.5 cm / min; Detection: 280 nm (reference 600 nm); Sample solution: 1% m / v; and

Gradient: time 0 min: 10% B

5 min: 10% B 7 min: 15% B

Λ

10 min: 47% B

15 min: 90% B.

The content of impurities was assessed on the assumption that each impurity at 280 nm had an absorbance as compound A.

Samples showing significant discoloration were further analyzed spectrophotometrically at 486 nm and the adrenochrome content was estimated from the value.

The results are shown in Tables 1 and 2 below, where the content of impurities is given as% m / m relative to Compound A, based on area percent integration, and where the retention times of the HPLC components are given in minutes.

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RESULTS

Table 1. Stability after 1 day pH 2 pH 4__pH 8. 3.7 * 60 * 37 * € 0 * 37 * | 60 · 5 Appearance Clear Clear ^ e ~ Gray-green bdf.

Adrenochrome (e |) - 0.11 0.34 * * i *! tiELOaæBSDfinliBtl Λ „

Unknown (2.9) - 0 »03 0.16

Unknown (3.1) * 0 * 05 10 Unknown (3.5) ”0» 03

Unknown (11 »1) 0 * 02 0.15

Unknown (11.6) Λ 0.05 0.38

Adrenochrome (12.5) - - 0.17 0.29 0.07 0.05

Unknown (13.5) - 0.05

Unknown (14.8) 0.03

Adrenolutin (15.2) 0.11 0.10 0.11 0.09 2.17 2.42 15 unknown (15.8) 0.31 0.47

Table 2. Stability after 5 days pH 2 pH 4 pH 8 20 37 * 60 * 37 * 60 * 37 * 60 *

Pale- Pink- Gray- big

Appearance Clear pink brown brown gray green bdf.

Adrenochrome (Ej) - 0.11 0.43 1.46 * * 25 HPLC component (Rt)

Unknown (2.9) - 0.04 0.15 0.70

Unknown (3.1) - 0.04

Unknown (3.5) - - 0.03 0.31

Unknown (10.3) - 0.06

Unknown (11.6) 0.04 0.05

Adrenochrome (12.5) - 0.10 0.31 0.21 0.17 0.14 Unknown (12.0) 0.18 0.28

Unknown (13.1) - - - 0.11

Unknown (13.5) - - - 0.08

Adrenolutin (15.2) .... 2.31 5.23

Unknown (15.8) 0.18 0.95 35 * Precipitation of the free amine in solutions of pH 8 prevented a spectrophotometric determination of adrenochrome.

Claims (6)

Pharmaceutical composition in the form of an aqueous solution suitable for freeze-drying, characterized in that it contains as an active ingredient 0.5-10% w / v (measured as the hydrochloride salt) of 4- [2- ( 6- (2-phenylethylamino) hexylamino) ethyl] -1,2-benzenediol or 4- [2- (6- (2- (4-chlorophenyl) ethylamino) -hexylamino) ethyl] -1,2-benzenediol or a pharmaceutically acceptable acid addition salt thereof and a physiologically acceptable acid, the pH of the solution being higher than 1.5 and lower than 3.5. A solution according to claim 1, characterized in that the active ingredient is in the form of an acid addition salt. DK 162508 B A solution according to claim 1 or 2, characterized in that the active ingredient is 4- [2- (6- (2-phenylethylamino) hexylamino) ethyl] -1,2-benzenediol dihydrochloride. Unit pack containing a solution according to any one of claims 1-3, characterized in that the pack contains from 10 to 500 mg (determined as hydrochloride salt) of the active ingredient. Process for preparing a solid form of the active ingredient, characterized in that an aqueous solution according to any one of claims 1-4 is freeze-dried. 5 At pH 4, all solutions showed signs of discoloration that were more evident in all cases than similar solutions at pH 2. HPLC analysis showed that adrenochrome and two unknown components with Rt 2.9 and 3.5 min were the most important degradation products, especially in samples stored at elevated temperature. At pH 8, excretion of the free amine was observed, preventing a spectrophotometric examination of the samples. HPLC showed many unidentified degradation products, and all samples clearly showed 15 more adrenolutin than could be observed at pH 2 or 4. The experiments clearly show the influence of pH on the stability of aqueous solutions of the invention (acidic pH) and in pH ranges outside the area that the discovery requires. 6. Freeze-dried composition, characterized in that it contains the active ingredient prepared by the method of claim 5.